Portal hypertension (PHT) and its complications account for over 100,000 deaths in the United States, making it one of the top four causes of death. Due to our lack of understanding of the etiology of the altered vasoregulation in PHT, treatment has not been directed at reversing these abnormalities. This proposal will determine the receptor and G-protein- linked signal mechanism alterations mediated by nitric oxide and prostacyclin, the two peptide hormones judged most responsible for the vascular hyperemia of PHT. The relationship between increased shear stress and/or pressure and the altered vasoregulation in PHT will also be assessed. A rat model of PHT will be used, together with vascular smooth muscle cells (VSMC) in static culture and co-cultures of VSMG, and endothelial cells exposed to variable shear stress and/or pressure. These experiments should provide valuable information central to our understanding of PHT and vasoregulation in other vascular hypertensive events.